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cancers Article Identification of Cancer Hub Gene Signatures Associated with Immune-Suppressive Tumor Microenvironment and Ovatodiolide as a Potential Cancer Immunotherapeutic Agent Jia-Hong Chen 1,2, Alexander T. H. Wu 3,4,5,6 , Bashir Lawal 7,8 , David T. W. Tzeng 9, Jih-Chin Lee 10, Ching-Liang Ho 2 and Tsu-Yi Chao 1,2,11,12,* 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; [email protected] 2 Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defence Medical Center, Taipei City 114, Taiwan; [email protected] 3 The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; [email protected] 4 Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan 5 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan 6 Taipei Heart Institute (THI), Taipei Medical University, Taipei 11031, Taiwan 7 PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; [email protected] 8 Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei, Medical University, Taipei 11031, Taiwan 9 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong; [email protected] Citation: Chen, J.-H.; Wu, A.T..H.; 10 Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Lawal, B.; Tzeng, D.T.W.; Lee, J.-C.; Medical Center, 325 Cheng-Kung Road Section 2, Taipei City 114, Taiwan; [email protected] Ho, C.-L.; Chao, T.-Y. Identification of 11 Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University-Shuang Cancer Hub Gene Signatures Ho Hospital, New Taipei City 235, Taiwan Associated with Immune-Suppressive 12 Taipei Cancer Center, Taipei Medical University, Taipei City 11031, Taiwan Tumor Microenvironment and * Correspondence: [email protected] Ovatodiolide as a Potential Cancer Immunotherapeutic Agent. Cancers Simple Summary: In order to identify common genes associated with the pathology of multiple 2021, 13, 3847. https://doi.org/ cancers, we integrated differential expressed gene (DEGs) from datasets of six cancers (liver, lung 10.3390/cancers13153847 colorectal, gastric, prostate, and breast cancers) and identified six DEGs common to the six cancers. We conducted enrichment analysis and our results suggested that the DEGs are involved in the Academic Editors: Alan Hutson and tumorigenic properties, including distant metastases, treatment failure, and survival prognosis. Song Liu Notably, our results suggested high frequencies of genetic and epigenetic alterations of the DEGs in association with tumor staging, immune evasion, poor prognosis, and therapy resistance. Transla- Received: 9 June 2021 Accepted: 27 July 2021 tionally, we intended to identify a drug candidate with the potential for targeting the DEGs. Using a Published: 30 July 2021 molecular docking platform, we estimated that ovatodiolide, a bioactive anti-cancer phytochemical, has high binding affinities to the binding pockets of the hub genes and thus could serve as a potential Publisher’s Note: MDPI stays neutral drug candidate for targeting the DEGs. with regard to jurisdictional claims in published maps and institutional affil- Abstract: Despite the significant advancement in therapeutic strategies, breast, colorectal, gastric, iations. lung, liver, and prostate cancers remain the most prevalent cancers in terms of incidence and mortality worldwide. The major causes ascribed to these burdens are lack of early diagnosis, high metastatic tendency, and drug resistance. Therefore, exploring reliable early diagnostic and prognostic biomarkers universal to most cancer types is a clinical emergency. Consequently, in the present Copyright: © 2021 by the authors. study, the differentially expressed genes (DEGs) from the publicly available microarray datasets of Licensee MDPI, Basel, Switzerland. six cancer types (liver, lung colorectal, gastric, prostate, and breast cancers), termed hub cancers, This article is an open access article were analyzed to identify the universal DEGs, termed hub genes. Gene set enrichment analysis distributed under the terms and (GSEA) and KEGG mapping of the hub genes suggested their crucial involvement in the tumorigenic conditions of the Creative Commons properties, including distant metastases, treatment failure, and survival prognosis. Notably, our Attribution (CC BY) license (https:// results suggested high frequencies of genetic and epigenetic alterations of the DEGs in association creativecommons.org/licenses/by/ with tumor staging, immune evasion, poor prognosis, and therapy resistance. Translationally, we 4.0/). Cancers 2021, 13, 3847. https://doi.org/10.3390/cancers13153847 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3847 2 of 20 intended to identify a drug candidate with the potential for targeting the hub genes. Using a molecular docking platform, we estimated that ovatodiolide, a bioactive anti-cancer phytochemical, has high binding affinities to the binding pockets of the hub genes. Collectively, our results suggested that the hub genes were associated with establishing an immune-suppressive tumor microenvironment favorable for disease progression and promising biomarkers for the early diagnosis and prognosis in multiple cancer types and could serve as potential druggable targets for ovatodiolide. Keywords: cancer hub; tumor microenvironments; onco-immune profiling; differentially expressed genes; ovatodiolide; cancer immunotherapy 1. Introduction The current global burden of cancer was estimated to be 19.3 million cases in 2020 and is expected to be 28.4 million cases in 2040 [1], a 47% rise from 2020. In line with the previous trend [2,3], the 2020 global cancer statistic report of cancer incidences and mortality indicate that breast (11.7% and 6.9%), lung (11.4% and 18%), colorectal (10.0% and 9.4%), prostate (7.3% and 3.8%), stomach (5.6% and 7.7%), and liver (4.7% and 8.3%) cancers are the most commonly diagnosed and the leading cause of cancer mortality globally [1]. With the exception of prostate and breast cancers, which are sex-specific, the prevalence and mortality rates of these cancers combined were higher in men than in women, at 45.5% and 42.1%, respectively. These six cancers, which constituted 50.7% and 54.1% of the total global cases and cancer deaths, respectively, are the primary focus of the current study and are collectively referred to as hub cancers hereafter. Therefore, it is crucial to identify the promising early diagnostic and prognostic biomarkers that may assist in elucidating the underlying molecular mechanisms of these cancers and simultaneously improve the clinical therapeutics [4]. Microarray technology and bioinformatics analysis have become a promising and valuable tool for screening significant genetic or epigenetic variations that occur during carcinogenesis and understanding the pathogenesis of the diseases for effective diagnosis, prognosis and planning adequate therapeutic strategies [5–8]. However, the outcome from most of these findings has not yielded significant translational success in predicting reliable universal biomarkers for the diagnosis and prognosis of the hub cancers. Thus, independent analysis of microarray and RNAseq data from different cancer datasets with subsequent integration of differentially expressed genes (DEGs) across the cancer types may help identify the universal markers concordant across multiple cancer studies with increased confidence and translational relevance to the clinics. In addition to the lack of reliable and early diagnostic biomarkers, the resistance to chemotherapy and adverse effects associated with chemotherapeutic agents currently use in clinics are jointly responsible for the poor prognosis of the hub cancer patients [9,10]. Therefore, there is an urgent need to develop new, affordable, effective and safer anticancer drugs [11]. Ovatodiolide, is a phytochemical isolated from Anisomeles indica (L.) Kuntze [12]. This plant originates from Taiwan and is commonly known as “Fang Feng Cao” by the traditional Taiwanese herbalist where it is commonly used as an oral remedy for stom- achache, swelling, abdominal pain, hypertension, arthritis, immunodeficiency disease, hepatic diseases, hemorrhoids, and arthritis [13]. The plant has been reported for various biological activities, including analgesic, anti-inflammatory, antimicrobial, hypotensive, hepatoprotective, and anti-proliferative activities [14]. Ovatodiolide has been identified as the major bioactive compound responsible for the biological activities of this plant and has been previously isolated and evaluated for anti-cancer activities against several human can- cer cell lines [12]. In our previous studies, we found that ovatodiolide sensitizes aggressive human cancer cells to chemotherapy and ameliorates the cancer stemness phenotype and chemotherapy-associated toxicity in an in vitro or/and in vivo models of breast cancer [15], glioblastoma [16], oral squamous cell carcinoma [17,18], colon cancer [19], and nasopha- Cancers 2021, 13, 3847 3 of 20 ryngeal carcinoma [20]. Studies elsewhere have also reported ovatodiolide for significant anti-cancer activities against hepatic cancer stem
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